Intratumoral hypoxia is an important predictor of tumor response to radiation therapy (RT). Not only does intratumoral hypoxia reduce the amount of molecular oxygen available for radiation-induced DNA damage, but hypoxia also alters a variety of cellular signaling pathways by stabilizing hypoxia- inducible factors HIF-1 and HIF-2. Elegant in vitro studies have shown that HIF-1 and HIF-2 play opposing roles in tumor cell response to RT. To study the role of HIFs in tumor response to RT in vivo, I have deleted HIFs in a novel primary mouse model of soft tissue sarcoma with conditional activation of oncogenic RAS and deletion of p53. In this proposal, I will determine how deletions of HIF-1 and/or HIF-2 in primary sarcomas affect RT response. Furthermore, by performing metabolomic-profiling on non-irradiated and irradiated tumors, I will determine how HIF-deficiency mediates changes in tumor response to RT via alterations in tumor metabolism. My long-term goal is to use this knowledge to develop novel therapies that may be administered with RT to improve tumor cure.